Total synthesis of mersicarpine through a cationic cyclization approach

Article abstract of DOI:10.1021/ol500308e

A concise total synthesis of mersicarpine is achieved by exploiting a cyclic carbamate for generation of a tertiary carbocation. The key step involves intramolecular Friedel-Crafts alkylation with this carbocation for the construction of a quaternary carbon center and a subsequent oxidation and cyclization cascade for the formation of a seven-membered cyclic imine. The chemistry allowed for a rapid one-pot synthesis of mersicarpine from a simple intermediate using straightforward chemical operations.

Full text of DOI:10.1021/ol500308e

Letter
pubs.acs.org/OrgLett
Total Synthesis of Mersicarpine through a Cationic Cyclization
Approach
Zhe Lv, Zining Li, and Guangxin Liang*
State Key Laboratory and Institute of Elemento-organic Chemistry, Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin, China, 300071
S
* Supporting Information
ABSTRACT: A concise total synthesis of mersicarpine is achieved by exploiting a cyclic carbamate for generation of a tertiary
carbocation. The key step involves intramolecular Friedel−Crafts alkylation with this carbocation for the construction of a
quaternary carbon center and a subsequent oxidation and cyclization cascade for the formation of a seven-membered cyclic
imine. The chemistry allowed for a rapid one-pot synthesis of mersicarpine from a simple intermediate using straightforward
chemical operations.
ersicarpine (1, Figure 1) is a structurally intriguing
monoterpene indole alkaloid isolated from the Kopsia
tetracyclic azepinoindole they observed also facilitated two
other asymmetric syntheses achieved by the groups of
Tokuyama5e,f and Zhu.5g
Driven by our continuous interest in the total synthesis of
mersicarpine,6 we conceived an appealing cationic polycycliza-
tion strategy toward this target (Scheme 1). Given that
M
Scheme 1. Original Synthetic Design of a Cationic
Polycyclization Strategy towards Mersicarpine
Figure 1. Molecular structures of mersicarpine, melodinine E, and
leuconolam.
species of plants by Kam and co-workers in 2004.1 Other than
the indoline moiety, this unusual tetracyclic natural product
possesses an atypical seven-membered cyclic imine and a δ-
lactam around a fully substituted hemiaminal stereogenic
center. Adjacent to the hemiaminal is a synthetically challenging
all-carbon quaternary center. Biosynthetically, mersicarpine
shares the same biogenetic origin as melodinine E,2 2, and
leuconolam,3 3, from vincadifformine.4 It was proposed that
leuconolam is a biosynthetic precursor of melodinine E which
further produces mersicarpine through skeleton rearrangement
and the loss of two carbons in the form of acetic acid.1
The unique structural feature of mersicarpine as well as its
interesting biosynthetic relationship to other alkaloids has
prompted many elegant solutions to the total synthesis of this
molecule.5 To date, two total syntheses and four formal
syntheses have been reported. Kerr and co-workers disclosed
the first total synthesis of mersicarpine in 2008 based on an
elegant malonic radical addition to indole for the construction
of the all-carbon quaternary center.5a A late stage key
intermediate in their synthesis inspired two formal total
syntheses from both Zard’s5b and Han’s5c groups. Fukuyama
and co-workers accomplished the first asymmetric total
synthesis of (−)-mersicarpine.5d The autoxidation of a
compound 4 has been reported to be an advanced intermediate
leading to mersicarpine through autoxidation and subsequent
reduction,5d−g we considered it as a primary synthetic target.
Presumably, compound 4 would be readily transformed from 5
through an enamine forming reaction. We envisioned that 5
could be made through an intramolecular Friedel−Craft
alkylation7 in a reactive cationic intermediate 6 if the protecting
group on oxygen tends to fall off under the reaction conditions.
To produce the critical cationic species, we decided to take
advantage of the carbamate functionality in 7. We assumed that
Received: January 28, 2014
Published: February 20, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
7 would produce 6 upon treatment with a Lewis acid to trigger
a facile Friedel−Craft cyclization to form the δ-lactam.
Subsequent loss of carbon dioxide and acidity adjustment of
the reaction media will generate a free amine in 5 for further
cyclization. What is worth noting is that although the carbamate
functionality has been widely used as protecting groups in
alkaloid chemistry, a tertiary carbocation derived from a
carbamate during deprotection of amines has hardly been
used for major bond forming reactions. This new application of
cyclic carbamate has the potential to facilitate a one-pot
synthesis of mersicarpine directly from 7 owing to the
consecutive reaction cascade.
Scheme 3. Syntheses of Substrates for Cationic
Polycyclization
conditions. As a result, the essential intermediate 6 was not
obtained in the reaction sequence.
In view of the fact that the current indole moiety in 7-I and
7-II was excessively labile under acidic conditions, we switched
to a new substrate carrying a more robust indole moiety to
explore the Friedel−Craft alkylation reaction. Chloroindole 16
(Scheme 4) was chosen owing to its stability under both basic
To investigate the aforementioned strategy, we devised a
rapid synthesis of 13 bearing the desired carbamate
functionality commencing from a readily available compound
8 (Scheme 2).8 After the carboxylic acid was inactivated
Scheme 2. Preparation of the Intermediate 13
Scheme 4. Total Synthesis of Mersicarpine
and acidic reaction conditions showcased in our total synthesis
of isatisine A.13 Indeed, the use of 16 in the coupling reaction
resulted in the production of 17 in 66% yield, significantly
higher than the yield of reactions using 14 and 15. More
importantly, the key Friedel−Crafts alkylation reaction was
fulfilled by using the new substrate which eventually led to our
total synthesis of mersicarpine. The natural product was
isolated in 25% yield after 17 was sequentially treated with
aluminum trichloride, a mixture of trifluoroacetic acid and
hydrogen peroxide, and sodium sulfite/sodium bicarbonate for
acidity optimization. To evaluate the efficiency of the Friedel−
Crafts alkylation, we closely monitored the reaction and
observed that it went to completion in 5 min with the product
18 isolated in 86% yield. Upon oxidation of 18 and acidity
optimization, mersicarpine was produced in 42% yield. Notably,
the 1H NMR data of our synthetic sample did not match those
reported for the natural material. The same observation by Kerr
and co-workers was reported in their first total synthesis of
mersicarpine. Through a careful titration experiment, they
through deprotonation by sodium hydride, 8 was converted to
9 upon treatment with an allyl Grignard reagent. Initially, we
anticipated that 11 could be produced from 9 in a single step
upon its conversion to an acyl azide. More specifically, the acyl
azide was expected to undergo a Curtius rearrangement9 to
generate an isocyanate intermediate which could be captured
by the tertiary alcohol to produce 11 directly. However, when
we carried out the reaction with 1 equiv of diphenyl
azidophosphate in the presence of N-methylmorpholine in
toluene,10 the reaction could not go to completion and 10 was
isolated as a major product in nearly 40% yield. Presumably, the
azide ion dissociated from diphenyl azidophosphate in the
presence of N-methylmorpholine reacted with the isocyanate
intermediate faster than the tertiary hydroxyl group. Only when
we used 2.5 equiv of diphenyl azidophosphate did the reaction
achieve completeness. We then achieved the synthesis of 11
from 9 in an overall yield of 53% through an additional step
under basic conditions. Hydroboration−oxidation11 of 11
followed by Jones oxidation on 12 afforded the desired
intermediate 13 in good yield.
Originally, we assumed that a silyl protecting group would
easily fall off after the key Friedel−Crafts alkylation reaction
occurs, which could facilitate the transformation from 7 to 4.
Although in low yield, we managed to prepare two substrates
bearing TBS (7-I) and TIPS (7-II) from 14 and 15,12
respectively, using CDI to activate 13 (Scheme 3). However,
neither 14 nor 15 gave the desired product upon treatment
with a variety of Lewis acids or Brønsted acids. In most cases,
the substrates decomposed under the reaction conditions. We
reasoned that the acid-sensitive indole moiety in 7-I and 7-II
could not survive activation of the carbamate under acidic
1
claimed that the H NMR spectra of mersicarpine are very
1
sensitive to solvent acidity, which caused variation in the H
NMR resonances.5a By using Kerr’s protocol, we obtained both
1H and 13C NMR data of our synthetic sample and found they
were in agreement with those acquired in base-washed CDCl3
by Kerr and co-workers, which verified the identity of our
synthetic sample.14
In summary, we have achieved a short synthesis of
mersicarpine based on a cationic cyclization strategy. A new
application of the carbamate functionality enabled production
of a carbocation species bearing a masked amine. An
intramolecular Friedel−Crafts alkylation of chloroindole with
the carbocation species fulfilled the facile construction of an all-
carbon quaternary center in mersicarpine. With subsequent
oxidation and optimization of acidity, the synthetic sequence
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Organic Letters
Letter
rapidly expanded the molecular complexity, leading to a one-
pot transformation of 17 to mersicarpine through simple
chemical operations.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and procedures, compound character-
1
ization data, copies of H and 13C NMR spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lianggx@nankai.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China,
Tianjin Natural Science Foundation (Grant No.
12JCZDJC26400), and the ‘111’ project (B06005) of the
Ministry of Education of China for financial support.
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